Immunoglobulins, monoclonal antibodies (mAbs) and humanized antibodies have been in development as pharmaceutical products for a number of years. There is a clear incentive for developing high concentration liquid formulations of mAbs due to the potential of subcutaneous administration which results in higher convenience for the patient. However, there is a general consensus that development of high-concentration formulations of mAbs poses serious challenges with respect to the physical and chemical stability of the mAb such as increased formation of soluble as well as insoluble aggregates which enhance the probability of an immunogenic response as well as give rise to low bioactivity.
Aggregate formation by a polypeptide during storage of a liquid pharmaceutical composition can adversely affect biological activity of that polypeptide, resulting in loss of therapeutic efficacy of the pharmaceutical composition. Furthermore, aggregate formation may cause other problems such as blockage of tubing, membranes, or pumps when the polypeptide-containing pharmaceutical composition is administered using an infusion system.
Furthermore, high-concentration formulations of mAbs have been reported to result in increased viscosity thereby creating serious challenges for the manufacturability and injectability.
Controlling aggregation and viscosity of liquid formulations of high-concentration mAbs is not a trivial matter. The fact that only few mAb product on the market exists as a high concentration liquid formulation (≧100 mg/ml) displays the complexity. Papers have been published which show that NaCl may lower the viscosity and also to some extent control aggregation (EP 1981824). Sucrose has also shown to stabilise mAb against formation of aggregates by way of a preferential exclusion mechanism. However, identifying suitable stabilisers is still an empirical science in this field.
It is well known that relatively high amounts of electrolytes, such as salt and buffer, are used to lower the viscosity of high concentration mAb formulations (EP 1981824). WO 01/24814 (Chiron Corporation) describes liquid polypeptide-containing pharmaceutical composition comprising an amino acid base as a stabiliser. EP 1336410 (Chugai Seiyaku Kabushiki Kaisha) describes an injectable pharmaceutical formulation containing a physiologically active protein and at least one sugar as a soothing agent. EP 1314437 (Chugai Seiyaku Kabushiki Kaisha) describes an antibody containing preparation comprising a glycine and/or histidine buffer. WO 02/30463 (Genentech, Inc) describes a concentrated protein formulation having reduced viscosity and a salt and/or buffer in an amount of at least about 50 mM. EP 1475100 (Chugai Seiyaku Kabushiki Kaisha) describes an antibody containing solution comprising an organic acid and a surfactant as stabilisers. EP 1475101 (Chugai Seiyaku Kabushiki Kaisha) describes an antibody containing solution comprising a sugar as a stabiliser. WO 2004/001007 (IDEC Pharmaceuticals Corporation) describes a concentrated antibody composition consisting essentially of histidine or acetate buffer in the range of from about 2 mM to about 48 mM. WO 2004/016286 (Abbot Laboratories (Bermuda) Ltd.) describes a formulation of human antibodies having a pH of between about 4 and 8. WO 2005/123131 (Medimmune Vaccines, Inc) describes a formulation for spray drying an antibody or vaccine. WO 2007/003936 (Insense Limited) describes a stable aqueous system comprising a protein and one or more stabilising agents which have ionisable groups. WO 2007/092772 (Medimmune, Inc.) describes a liquid protein formulation comprising an Fc variant protein and between 1 mM to 100 mM buffering agent. US 2004/0022792 (Immunex Corporation) describes a method of stabilising a protein at a pH of between about 2.8 and about 4.0. US 2003/0180287 (Immunex Corporation) describes an aqueous pharmaceutical composition suitable for long term storage of polypeptides. WO 2008/071394 (F. Hoffmann-La Roche AG) describes a stable pharmaceutical parenteral formulation containing an antibody. WO 2009/120684 and WO 2008/121615 (MedImmune Inc) both describe high concentration liquid formulations of antibodies or fragments thereof that specifically bind to a human interferon alpha polypeptide. WO 2009/070642 (MedImmune Inc) describes stable lyophilized formulations of bispecific antibodies or fragments thereof. EP 1 977 763 (Chugai Seiyaku Kabushiki Kaisha) describes antibody containing stabilising compositions comprising one or more amino acids. US 2004/0197324 (Genentech, Inc) describes highly concentrated antibody and protein formulations with reduced viscosity. WO 2008/132439 (University of Strathclyde) describes precipitation stabilising compositions which are claimed to prevent or reduce aggregation. US 2007/0020255 (Kyowa Hakko Kogyo Co., Ltd) describes a method of stabilising an antibody in solution which comprises the addition of glycine and citric acid to the solution. US 2007/0184050 (Kirin Beer Kabushiki Kaisha) describes a stable liquid formulation containing an antibody in a glutamate buffer and/or a citrate buffer. US2009/0280129 (Genentech describes high concentration antibody and protein formulations.
There is therefore a great need for a stable high-concentrated pharmaceutical antibody composition having a low and feasible viscosity which is suitable for subcutaneous administration, such as in a ready to use device. Furthermore, from a patient point of view it would be highly desirable to have room temperature stable products. At this moment, there are no marketed mAb formulations where storage at room temperature is a possibility throughout the shelf life of the drug product. Typically, increased protein degradation occurs forming an un-acceptably high level of aggregates and protein related impurities, which may give rise to immunogenic reactions.
Many of the marketed mAb products contain surfactants in their formulation. Typically, surfactants are added in order to reduce interfacial stress which can induce protein aggregation and particle formation leading to unacceptable product quality. Examples of interfacial stress could be contact of the protein with i) air ii) container closure material, such as rubber plunger, piston, glass, pre-filled syringes iii) production related materials, such as steel tanks, tubings and pumps iv) ice, during freeze/thaw, etc. However, surfactants such as polysorbates typically contain a residue of peroxides which may oxidize the protein molecule leading to a compromised product quality. Furthermore, from a manufacturing point of view addition of polysorbates requires an extra step in the production since ultra/diafiltration is challenging to conduct when the formulation contains the said polysorbates. The formation of oxidized products is a challenging issue, therefore a careful handling of polysorbates is required in order to control the formation of oxidized products. Thus, it would be desirable to design formulations without surfactants, both from a stability- and manufacturing point of view.